Antonio Vittoria

TOWARD A QUANTITATIVE COMPARATIVE TOXICOLOGY OF ORGANIC COMPOUNDS

Correlation equations between logP (P = octanol water partition coefficient) and the biological activity of alcohols has been derived for 101 examples on all sorts of systems, from simple proteins to whole animals. This provides an overview of the toxic nature of hydrophobic compounds which can be used as a basis for comparison of more complex chemicals. About 100 examples of the hydrophobic effects of chemicals, other than alcohols, to various living systems or their parts are presented for comparison. It is clear that hydrophobic xenobiotics are toxic to almost every form of life, including humans (or parts there of).

Quantitative structure-activity relationships of chymotrypsin-ligand interactions: An analysis of interactions in ϱ3 space

Abstract Fourteen derivatives of l -alanine of the type CH 3 CH(NHCO-3-C 5 H 4 N)COOR 3 have been synthesized and their hydrolysis by chymotrypsin was studied with the object of characterizing enzymic space ( ϱ 3 ) to which R 3 binds. The binding of R 3 ( log 1 K m ) was shown via correlation analysis to correlate with molar refractivity (MR) of R 3 rather than hydrophobicity (π). The results confirmed our earlier predictions. A correlation equation for the hydrolysis of 77 acyl-amino acid esters of the general formula R 2 CH(NHCOR 1 )COOR 3 relating log (k cat k m ) to molar refractivity of R 1 , R 2 , and R 3 and to σ ∗ (Tafts polar parameter) of R 3 was formulated. The general picture of ligand interactions with chymotrypsin as seen with correlation analysis is discussed.

Use of the hydrogen bond potential function in a comparative molecular field analysis (CoMFA) on a set of benzodiazepines

SummaryThe results of the GRID-Comparative Molecular Field Analysis (CoMFA) were compared with those of the SYBYL-CoMFA in a study of benzodiazepines. The results demonstrate that the hydrogen bonding function using the GRID H2O probe in a CoMFA can successfully describe the hydrophobic effects of substituents without any bias or preconcept of their effects in the development.

Inhibition of chymotrypsin by alkyl phosphonates: a quantitative structure-activity analysis.

Abstract A quantitative structure-activity relationship has been formulated for 53 alkyl phosphonates [R2OPO(CH3)SR3] inhibiting chymotrypsin: log k i = 1.47 MR OR 2 + 0.34 MR SR 3 + 1.25 σ 3 ∗ − 1.06I − 3.43 log (β·10 MR OR 2 + 1) − 5.26; log β = −3.85 . In this so-called bilinear model, ki is the bimolecular rate constant ( m −1 s−1), β is a disposable parameter evaluated by a computerized iterative procedure, MR is the molar refractivity of a substituent, σ 3 ∗ is Tafts polar parameter, and I is an indicator variable for substituents containing a sulfonium group. The correlation coefficient for this equation is 0.985. This quantitative structure-activity relationship is compared with those previously formulated for the action of chymotrypsin on acylamino acid ester substrates.

Effects of variable selection on CoMFA coefficient contour maps in a set of triazines inhibiting DHFR

SummaryAn example of a CoMFA study is described with the aim to discuss one of the major problems of this 3D QSAR method: lack of variable selection. It is shown that the use of nonrelevant energy parameters might produce CoMFA contour maps which poorly reflect the actual nature of the binding site and are in part statistical artefacts. The data set employed in our analysis comparises triazine inhibitors of dihydrofolate reductase (DHFR), isolated from chicken liver, which have already been the object of a QSAR study by other authors. Since three-dimensional structures of triazine-DHFR complexes are known, it was possible not only to reduce ambiguities in the superimposition of the ligands, but also to compare the resulting CoMFA contour maps with the enzyme active site.

Of Poisons and Antidotes in Polypropylene Catalysis

Quenched-flow studies of MgCl2 -supported Ziegler-Natta catalysts were combined for the first time with (13) C NMR fingerprinting of the nascent polymer and conclusively proved that, depending on the catalyst formulation, propene polymerization can be slowed down significantly by the occurrence of the few regiodefects (2,1 monomer insertions), changing active sites into dormant sites. Catalysts modified with ethylbenzoate show little dormancy. The more industrially relevant phthalate based catalysts, instead, are highly dormant and require the presence of H2 to counteract the deleterious effect of this self-poisoning on productivity and stereoselectivity.

Internal Donors in Ziegler-Natta systems: is reduction by AlR3 a requirement for donor clean-up?

Alkyl benzoates, phthalates, and succinates are used as “internal donors” (ID) to modify the surface of MgCl2‐supported Ziegler–Natta (ZN) catalysts for polypropylene production. Phthalates, in particular, are the working horses of this catalysis, but a REACH ban of these compounds for other applications has generated a desire from the market for phthalate‐free ZN catalysts, which has in turn triggered a search for alternatives and revamped research in the area. It has been reported that under polymerization conditions certain ID classes undergo an extensive exchange with alkoxysilane “external donors” (ED), which represents an important opportunity for surface fine‐tuning. ID clean‐up has been attributed to ester group reduction by the AlR3 cocatalyst. We have now measured the activation parameters for the reactions of ethyl benzoate (EB), dibutyl phthalate (DBP), and diethyl 2,3‐diisobutylsuccinate (DiBS) with AlEt3 in toluene solution by means of variable‐temperature 1H NMR spectroscopy. Reduction is fast for EB and DBP, whereas it is slow for DiBS. Results of DFT calculations are in line with the observed reactivity. Therefore, we conclude that an irreversible reaction with AlEt3 is not the only option for ID/ED exchange. Possible alternatives are discussed.

Solid-state structure and conformation of (Z)-2-(phenylbenzylidene)-3-quinuclidinone, an intermediate in the synthesis of quinuclidine derivatives

Abstract(Z)-2-(2-phenylbenzylidene)-3-quinuclidinone, C20H19NO,Mr=300.47D crystallizes in the monoclinicP21/c space group witha = 6.9809(2) Å,b=19.0523(2) Å,c = 11.7733(1) Å,β=100.92(2)°,V=1537.5(3) Å3,Z=4,Dc = 1.298 g/cm3,Dx=1.29 g/cm3 (flotation). Diffractometric data, using CuKα radiation,λ=1.54178 Å, were collected on plate-like crystals. The structure, solved by direct methods was refined to a final R value of 0.037 for the 2645 observed reflections withFo>3.0σ(Fo). The molecule shows a trans conformation around the double bond. The quinuclidine and the diphenyl moieties present deformations in their geometric and conformational parameters due to the need of releasing intramolecular strains and/or nonbonded interactions.

Assignment of Regioirregular Sequences in the 13C NMR Spectrum of Syndiotactic Polypropylene

The 13C NMR microstructure of a polypropylene (PP) sample is a fundamental source of information on its properties, and also a ‘fingerprint’ of the catalytic species used to produce it. Likely due to a much greater technological importance, isotactic polymers (i-PP) have been more thoroughly investigated that syndiotactic ones (s-PP). In this paper, we report the first full assignment of regioirregular sequences in s-PP samples made with two well-known molecular catalysts, namely a Cs-symmetric (cyclopentadienyl)(fluorenyl) ansa-zirconocene and a fluxional bis(phenoxyimine)Ti species. The results shed more light on the mechanism of chain propagation at the two catalysts, and open the door to the investigation of more elusive cases like the formation of s-PP blocks in the presence of multi-sited heterogeneous Ziegler-Natta systems.